Massari F.

Mollica V.

Rizzo A.

Santoni M.

English

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

Citation: Rizzo, A.; Mollica, V.;Santoni, M.; Massari, F. CancerImmunotherapy: Harnessing theImmune System to Fight Cancer. J.Clin. Med. 2022, 11, 6356. https://doi.org/10.3390/jcm11216356Received: 22 October 2022Accepted: 26 October 2022Published: 27 October 2022Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2022 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Journal ofClinical MedicineEditorialCancer Immunotherapy: Harnessing the Immune System toFight CancerAlessandro Rizzo 1,* , Veronica Mollica 2,3 , Matteo Santoni 4 and Francesco Massari 2,31 Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del PazienteOncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65,70124 Bari, Italy2 Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni-15,40138 Bologna, Italy3 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138 Bologna, Italy4 Medical Oncology Unit, Macerata General Hospital, 62100 Macerata, Italy* Correspondence: rizzo.alessandro179@gmail.comThe advent of cancer immunotherapy has represented an unprecedented revolutionin patients with hematological and solid tumors [1–3]. Immunotherapy with immunecheckpoint inhibitors (ICIs) has been suggested to induce durable and robust anticancerresponses in cancer patients [4–6]. For example, the treatment landscape for metastatic renalcell carcinoma (mRCC) has changed dramatically over the last decade, with the standard ofcare shifting from tyrosine kinase inhibitor (TKI) monotherapy to combination treatments,including ICIs [7,8]. In this genitourinary tumor, there are several approved immune-basedcombinations, including two ICIs or an ICI plus a multitarget TKI, and these treatmentshave significant clinical benefit compared to monotherapy [9–12]. Several successfulclinical trials have expanded the use of ICIs in an impressive number of solid tumors,ranging from urothelial carcinoma to gastric carcinoma, colorectal cancer, hepatocellularcarcinoma, and head and neck squamous cell carcinoma [13–19]. In addition, following theapproval in tissue-agnostic malignancies with microsatellite instability, the PD-1 inhibitorpembrolizumab became the first agent to be selectively approved according to a molecularbiomarker rather than by the primary tumor site [20,21].However, several questions regarding modern immunotherapy remain unanswered.Among these, ICIs present a specific set of treatment-related toxicities, which are commonlyknown as immune-related adverse events (irAEs) and are a result of the erroneous acti-vation of the immune system against self-antigens [22–24]. Several organ systems maybe affected by irAEs, including the thyroid, pancreas, and liver, with the incidence andseverity of irAEs depending on multiple factors, including the type of ICI, the tumor type,and the disease setting [25–27]. Another fundamental issue in current and future cancerimmunotherapy is the identification of reliable biomarkers of response or resistance [28,29].In fact, while ICIs have found their role in several tumors in monotherapy or as partof combinatorial strategies, the lack of validated biomarkers of response represents animportant issue, since not all cancer patients benefit from immunotherapy [30,31]. Basedon these concepts, a greater understanding of the role of potential biomarkers, includingprogrammed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), mi-crosatellite instability (MSI) status, gut microbiota, concomitant medications, and severalothers, is fundamental [32–40]. Additionally, clinical trials on cancer immunotherapy fre-quently differ in terms of drugs, patients, designs, terms of study phases, and inconsistentclinical outcomes.This Special Issue aims to highlight unanswered questions and future perspectivesin modern cancer immunotherapy, including novel immune checkpoint inhibitors andimmune-based combinations, mechanisms of action, potential biomarkers predictive ofresponse, experimental treatments, and other timely and emerging topics. InternationalJ. Clin. Med. 2022, 11, 6356. https://doi.org/10.3390/jcm11216356 https://www.mdpi.com/journal/jcmJ. Clin. Med. 2022, 11, 6356 2 of 3experts in this field will examine key approaches under active investigation in clinical andpreclinical research, presenting critical analyses and integrating their own perspectives onpromising drugs in clinical trials and the latest therapeutic strategies.Author Contributions: Conceptualization, A.R., V.M., M.S. and F.M.; methodology, A.R., V.M., M.S.and F.M.; software, A.R., V.M., M.S. and F.M.; validation, A.R., V.M., M.S. and F.M.; formal analysis,A.R., V.M., M.S. and F.M.; investigation, A.R., V.M., M.S. and F.M.; resources, A.R., V.M., M.S. andF.M.; data curation, A.R., V.M., M.S. and F.M.; writing—original draft preparation, A.R., V.M., M.S.and F.M.; writing—review and editing, A.R., V.M., M.S. and F.M.; visualization, A.R., V.M., M.S. andF.M.; supervision, A.R., V.M., M.S. and F.M.; project administration, A.R., V.M., M.S. and F.M.; fundingacquisition, all authors. All authors have read and agreed to the published version of the manuscript.Funding: This research received no external funding.Conflicts of Interest: The authors declare no conflict of interest.References1. Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al.Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell LungCancer With PD-L1 Tumor Proportion Score of 50% or Greater. J. Clin. Oncol. 2019, 37, 537–546. [CrossRef] [PubMed]2. Powles, T.; Walker, J.; Andrew Williams, J.; Bellmunt, J. The evolving role of PD-L1 testing in patients with metastatic urothelialcarcinoma. Cancer Treat. Rev. 2020, 82, 101925. [CrossRef] [PubMed]3. Massari, F.; Rizzo, A.; Mollica, V.; Rosellini, M.; Marchetti, A.; Ardizzoni, A.; Santoni, M. Immune-Based combinations for thetreatment of metastatic renal cell carcinoma: A meta-analysis of randomised clinical trials. Eur. J. Cancer. 2021, 154, 120–127.[CrossRef] [PubMed]4. Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Arén Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.;George, S.; et al. CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.N. Engl. J. Med. 2018, 378, 1277–1290. [CrossRef] [PubMed]5. Massari, F.; Mollica, V.; Rizzo, A.; Cosmai, L.; Rizzo, M.; Porta, C. Safety evaluation of immune-based combinations in patientswith advanced renal cell carcinoma: A systematic review and meta-analysis. Expert Opin. Drug Saf. 2020, 19, 1329–1338. [CrossRef]6. de Miguel, M.; Calvo, E. Clinical Challenges of Immune Checkpoint Inhibitors. Cancer Cell. 2020, 38, 326–333. [CrossRef]7. Motzer, R.J.; Rini, B.I.; McDermott, D.F.; Arén Frontera, O.; Hammers, H.J.; Carducci, M.A.; Salman, P.; Escudier, B.; Beuselinck, B.;Amin, A.; et al. CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advancedrenal cell carcinoma: Extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol.2019, 20, 1370–1385. [CrossRef]8. Rini, B.I.; Plimack, E.R.; Stus, V.; Gafanov, R.; Hawkins, R.; Nosov, D.; Pouliot, F.; Alekseev, B.; Soulières, D.; Melichar, B.; et al.KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J.Med. 2019, 380, 1116–1127. [CrossRef]9. Dizman, N.; Arslan, Z.E.; Feng, M.; Pal, S.K. Sequencing Therapies for Metastatic Renal Cell Carcinoma. Urol. Clin. N. Am. 2020,47, 305–318. [CrossRef]10. Massari, F.; Di Nunno, V.; Mollica, V.; Graham, J.; Gatto, L.; Heng, D. Adjuvant Tyrosine Kinase Inhibitors in Treatment of RenalCell Carcinoma: A Meta-Analysis of Available Clinical Trials. Clin. Genitourin Cancer 2019, 17, e339–e344. [CrossRef]11. Powles, T.; ESMO Guidelines Committee. Recent eUpdate to the ESMO Clinical Practice Guidelines on renal cell carcinoma oncabozantinib and nivolumab for first-line clear cell renal cancer: Renal cell carcinoma: ESMO Clinical Practice Guidelines fordiagnosis, treatment and follow-up. Ann. Oncol. 2021, 32, 422–423. [CrossRef] [PubMed]12. Thana, M.; Wood, L.A. What do International Guidelines Say about First-Line Therapy for Clear-Cell Metastatic Renal CellCarcinoma? Eur. Urol. Focus 2020, 6, 48–52. [CrossRef] [PubMed]13. Yang, Y. Cancer immunotherapy: Harnessing the immune system to battle cancer. J. Clin. Investig. 2015, 125, 3335–3337. [CrossRef]14. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.;Hassel, J.C.; et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711–723.[CrossRef]15. Hwu, P. Treating cancer by targeting the immune system. N. Engl. J. Med. 2010, 363, 779–781. [CrossRef]16. Ancevski Hunter, K.; Socinski, M.A.; Villaruz, L.C. PD-L1 Testing in Guiding Patient Selection for PD-1/PD-L1 Inhibitor Therapyin Lung Cancer. Mol. Diagn. Ther. 2018, 22, 1–10. [CrossRef]17. Santoni, M.; Massari, F.; Bracarda, S.; Grande, E.; Matrana, M.R.; Rizzo, M.; De Giorgi, U.; Basso, U.; Aurilio, G.; Incorvaia, L.; et al.Cabozantinib in Patients with Advanced Renal Cell Carcinoma Primary Refractory to First-Line Immunocombinations or TyrosineKinase Inhibitors. Eur. Urol. Focus 2022, 19. [CrossRef]18. Bergerot, P.; Lamb, P.; Wang, E.; Pal, S.K. Cabozantinib in Combination with Immunotherapy for Advanced Renal Cell Carcinomaand Urothelial Carcinoma: Rationale and Clinical Evidence. Mol Cancer Ther. 2019, 18, 2185–2193. [CrossRef]J. Clin. Med. 2022, 11, 6356 3 of 319. Cheng, A.L.; Hsu, C.; Chan, S.L.; Choo, S.P.; Kudo, M. Challenges of combination therapy with immune checkpoint inhibitors forhepatocellular carcinoma. J. Hepatol. 2020, 72, 307–319. [CrossRef] [PubMed]20. Lemery, S.; Keegan, P.; Pazdur, R. First FDA Approval Agnostic of Cancer Site—When a Biomarker Defines the Indication. N.Engl. J. Med. 2017, 377, 1409–1412. [CrossRef]21. Yarchoan, M.; Hopkins, A.; Jaffee, E.M. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N. Engl. J. Med. 2017,377, 2500–2501. [CrossRef]22. Santoni, M.; Rizzo, A.; Mollica, V.; Matrana, M.R.; Rosellini, M.; Faloppi, L.; Marchetti, A.; Battelli, N.; Massari, F. The impact ofgender on the efficacy of immune checkpoint inhibitors in cancer patients: The MOUSEION-01 study. Crit. Rev. Oncol. Hematol.2022, 170, 103596. [CrossRef] [PubMed]23. Rizzo, A.; Mollica, V.; Marchetti, A.; Nuvola, G.; Rosellini, M.; Tassinari, E.; Molina-Cerrillo, J.; Myint, Z.W.; Buchler, T.; Monteiro,F.S.M.; et al. Adjuvant PD-1 and PD-L1 Inhibitors and Relapse-Free Survival in Cancer Patients: The MOUSEION-04 Study.Cancers 2022, 14, 4142. [CrossRef] [PubMed]24. Hu, D.; Zhang, W.; Tang, J.; Zhou, Z.; Liu, X.; Shen, Y. Improving safety of cancer immunotherapy via delivery technology.Biomaterials 2021, 265, 120407. [CrossRef] [PubMed]25. Rizzo, A.; Ricci, A.D. Biomarkers for breast cancer immunotherapy: PD-L1, TILs, and beyond. Expert Opin. Investig. Drugs 2022,31, 549–555. [CrossRef]26. Rizzo, A.; Santoni, M.; Mollica, V.; Logullo, F.; Rosellini, M.; Marchetti, A.; Faloppi, L.; Battelli, N.; Massari, F. Peripheralneuropathy and headache in cancer patients treated with immunotherapy and immuno-oncology combinations: The MOUSEION-02 study. Expert Opin. Drug Metab. Toxicol. 2021, 17, 1455–1466. [CrossRef]27. Herzyk, D.J.; Haggerty, H.G. Cancer Immunotherapy: Factors Important for the Evaluation of Safety in Nonclinical Studies.AAPS J. 2018, 20, 28. [CrossRef]28. Rizzo, A.; Mollica, V.; Cimadamore, A.; Santoni, M.; Scarpelli, M.; Giunchi, F.; Cheng, L.; Lopez-Beltran, A.; Fiorentino, M.;Montironi, R.; et al. Is There a Role for Immunotherapy in Prostate Cancer? Cells. 2020, 9, 2051. [CrossRef]29. Sheng, I.Y.; Rini, B.I. Immunotherapy for renal cell carcinoma. Expert Opin. Biol. Ther. 2019, 19, 897–905. [CrossRef]30. Wang, Z.; Duan, J.; Cai, S.; Han, M.; Dong, H.; Zhao, J.; Zhu, B.; Wang, S.; Zhuo, M.; Sun, J.; et al. Assessment of Blood TumorMutational Burden as a Potential Biomarker for Immunotherapy in Patients with Non-Small Cell Lung Cancer With Use of aNext-Generation Sequencing Cancer Gene Panel. JAMA Oncol. 2019, 5, 696–702. [CrossRef]31. Santoni, M.; Bracarda, S.; Nabissi, M.; Massari, F.; Conti, A.; Bria, E.; Tortora, G.; Santoni, G.; Cascinu, S. CXC and CC chemokinesas angiogenic modulators in nonhaematological tumors. Biomed. Res. Int. 2014, 2014, 768758. [CrossRef] [PubMed]32. Goodman, A.M.; Kato, S.; Bazhenova, L.; Patel, S.P.; Frampton, G.M.; Miller, V.; Stephens, P.J.; Daniels, G.A.; Kurzrock, R. TumorMutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol. Cancer Ther. 2017,16, 2598–2608. [CrossRef] [PubMed]33. Santoni, M.; Massari, F.; Del Re, M.; Ciccarese, C.; Piva, F.; Principato, G.; Montironi, R.; Santini, D.; Danesi, R.; Tortora, G.; et al.Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer. Expert Opin.Investig. Drugs 2015, 24, 809–824. [CrossRef]34. Chalmers, Z.R.; Connelly, C.F.; Fabrizio, D.; Gay, L.; Ali, S.M.; Ennis, R.; Schrock, A.; Campbell, B.; Shlien, A.; Chmielecki, J.; et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017, 9, 34. [CrossRef]35. Mollica, V.; Santoni, M.; Matrana, M.R.; Basso, U.; De Giorgi, U.; Rizzo, A.; Maruzzo, M.; Marchetti, A.; Rosellini, M.; Bleve, S.; et al.Concomitant Proton Pump Inhibitors and Outcome of Patients Treated with Nivolumab Alone or Plus Ipilimumab for AdvancedRenal Cell Carcinoma. Target Oncol. 2022, 17, 61–68. [CrossRef] [PubMed]36. Santoni, M.; Buti, S.; Conti, A.; Porta, C.; Procopio, G.; Sternberg, C.N.; Bracarda, S.; Basso, U.; De Giorgi, U.; Rizzo, M.; et al.Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy.Target Oncol. 2015, 10, 517–522. [CrossRef]37. Rizzo, A.; Ricci, A.D.; Brandi, G. Durvalumab: An investigational anti-PD-L1 antibody for the treatment of biliary tract cancer.Expert Opin. Investig. Drugs 2021, 30, 343–350. [CrossRef]38. Di Nunno, V.; Frega, G.; Santoni, M.; Gatto, L.; Fiorentino, M.; Montironi, R.; Battelli, N.; Brandi, G.; Massari, F. BAP1 in solidtumors. Future Oncol. 2019, 15, 2151–2162. [CrossRef]39. Iacovelli, R.; Massari, F.; Albiges, L.; Loriot, Y.; Massard, C.; Fizazi, K.; Escudier, B. Evidence and Clinical Relevance of TumorFlare in Patients Who Discontinue Tyrosine Kinase Inhibitors for Treatment of Metastatic Renal Cell Carcinoma. Eur. Urol. 2015,68, 154–160. [CrossRef]40. Rizzo, A.; Ricci, A.D.; Gadaleta-Caldarola, G.; Brandi, G. First-Line immune checkpoint inhibitor-based combinations inunresectable hepatocellular carcinoma: Current management and future challenges. Expert Rev. Gastroenterol. Hepatol. 2021,15, 1245–1251. [CrossRef]

Cancer Immunotherapy: Harnessing the Immune System to Fight Cancer

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Cancer Immunotherapy: Harnessing the Immune System to Fight Cancer

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Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna